The long-term objectives of this research are to understand the molecular and metabolic events that are involved in the actions of glucocorticoid hormones on their target cells. This includes the elucidation of the intracellular regulatory mechanisms that operate physiologically to mediate changes in cellular metabolism and genetic expression as a background for understanding of the molecular mechanisms through which endocrine regulation is superimposed. During this next 5-year period the efforts will be directed to an analysis of the mechanisms through which glucocorticoids alter rates of protein biosynthesis at the level of translation. One of the objectives will be a rigorous examination of a hypothesis that some of the late (after 2 hrs of hormone exposure) inhibitory effects of glucocorticoid hormones on transport and synthetic reactions, including protein biosynthesis, are the cells' response to a glucocorticoid-induced inhibition of cellular ATP production, which in turn leads to small, steady-state changes in ratios of adenine nucleotides. The approach will be to first gain a better understanding of regulatory mechanisms in thymus cells by determining what shifts in rate-limiting reactions or components are responsible for the rapid changes in overall rates of protein synthesis that occur in response to small changes in ratios of adenine and nucleotides. We will then identify and try to understand the molecular mechanisms through which glucocorticoids produce their characteristic inhibitory effects by defining the mechanisms through which hormones interact with, or produce shifts in, these rate-limiting reactions or components.